BR112020013303B1 - N-ALKYL-N-CYANOALKYLBENZAMIDE COMPOUND OF GENERAL FORMULA I, INTERMEDIATE FOR THE PREPARATION OF AN N-ALKYLCYANOALKYLBENZAMIDE COMPOUND, METHOD FOR PREPARING A COMPOUND OF GENERAL FORMULA I WITH A COMPOUND OF GENERAL FORMULA II, PROCESS FOR PREPARING INSECTICIDES FOR CONTROL OF PESTS, INSECTICIDE COMPOSITION AND METHOD FOR CONTROLLING PESTS - Google Patents
N-ALKYL-N-CYANOALKYLBENZAMIDE COMPOUND OF GENERAL FORMULA I, INTERMEDIATE FOR THE PREPARATION OF AN N-ALKYLCYANOALKYLBENZAMIDE COMPOUND, METHOD FOR PREPARING A COMPOUND OF GENERAL FORMULA I WITH A COMPOUND OF GENERAL FORMULA II, PROCESS FOR PREPARING INSECTICIDES FOR CONTROL OF PESTS, INSECTICIDE COMPOSITION AND METHOD FOR CONTROLLING PESTS Download PDFInfo
- Publication number
- BR112020013303B1 BR112020013303B1 BR112020013303-5A BR112020013303A BR112020013303B1 BR 112020013303 B1 BR112020013303 B1 BR 112020013303B1 BR 112020013303 A BR112020013303 A BR 112020013303A BR 112020013303 B1 BR112020013303 B1 BR 112020013303B1
- Authority
- BR
- Brazil
- Prior art keywords
- compound
- general formula
- alkyl
- methyl
- chlorine
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 84
- 238000000034 method Methods 0.000 title claims description 19
- 239000000203 mixture Substances 0.000 title claims description 18
- 239000002917 insecticide Substances 0.000 title claims description 12
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 3
- 230000000749 insecticidal effect Effects 0.000 claims abstract description 22
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 11
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 37
- 239000000460 chlorine Substances 0.000 claims description 27
- 229910052801 chlorine Inorganic materials 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 125000005843 halogen group Chemical group 0.000 claims description 20
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 19
- 229910052794 bromium Inorganic materials 0.000 claims description 19
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 19
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 18
- -1 CH2CHF2 Chemical group 0.000 claims description 17
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 12
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 241000607479 Yersinia pestis Species 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 4
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 3
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 3
- UHCBBWUQDAVSMS-UHFFFAOYSA-N fluoroethane Chemical compound CCF UHCBBWUQDAVSMS-UHFFFAOYSA-N 0.000 claims description 3
- 125000006342 heptafluoro i-propyl group Chemical group FC(F)(F)C(F)(*)C(F)(F)F 0.000 claims description 3
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 239000001963 growth medium Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 8
- 239000002361 compost Substances 0.000 abstract description 4
- 125000001475 halogen functional group Chemical group 0.000 abstract 5
- 239000000243 solution Substances 0.000 description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 238000003786 synthesis reaction Methods 0.000 description 26
- 230000015572 biosynthetic process Effects 0.000 description 25
- 239000007787 solid Substances 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 241000238631 Hexapoda Species 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 241000500437 Plutella xylostella Species 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 6
- 240000007124 Brassica oleracea Species 0.000 description 5
- 241000098289 Cnaphalocrocis medinalis Species 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
- 235000003899 Brassica oleracea var acephala Nutrition 0.000 description 4
- 235000011301 Brassica oleracea var capitata Nutrition 0.000 description 4
- 235000001169 Brassica oleracea var oleracea Nutrition 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 241001147381 Helicoverpa armigera Species 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 241000985245 Spodoptera litura Species 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 230000000704 physical effect Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- NHSYMDAXWVRGII-UHFFFAOYSA-N 2-amino-N-(2-cyanopropan-2-yl)-N,3-dimethylbenzamide Chemical compound C(#N)C(C)(C)N(C(C1=C(C(=CC=C1)C)N)=O)C NHSYMDAXWVRGII-UHFFFAOYSA-N 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000011081 inoculation Methods 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 3
- XAYCTBDPZIKHCW-UHFFFAOYSA-N (3-chloropyridin-2-yl)hydrazine Chemical compound NNC1=NC=CC=C1Cl XAYCTBDPZIKHCW-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- JZNFOQXFZCNZJF-UHFFFAOYSA-N 2-amino-5-chloro-N-(2-cyanopropan-2-yl)-N,3-dimethylbenzamide Chemical compound C(#N)C(C)(C)N(C(C1=C(C(=CC(=C1)Cl)C)N)=O)C JZNFOQXFZCNZJF-UHFFFAOYSA-N 0.000 description 2
- YYRNCZUJHMUFGH-UHFFFAOYSA-N 2-amino-N-(2-cyanopropan-2-yl)-5-iodo-N,3-dimethylbenzamide Chemical compound NC1=C(C(=O)N(C)C(C)(C)C#N)C=C(C=C1C)I YYRNCZUJHMUFGH-UHFFFAOYSA-N 0.000 description 2
- BWWHTIHDQBHTHP-UHFFFAOYSA-N 2-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1C(Cl)=O BWWHTIHDQBHTHP-UHFFFAOYSA-N 0.000 description 2
- YVHZCFAUJFDIJY-UHFFFAOYSA-N 3-methyl-2-nitrobenzoyl chloride Chemical compound CC1=CC=CC(C(Cl)=O)=C1[N+]([O-])=O YVHZCFAUJFDIJY-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- CKAATYOECWZFCI-UHFFFAOYSA-N 5-chloro-2-(3-chloropyridin-2-yl)pyrazole-3-carboxylic acid Chemical compound OC(=O)C1=CC(Cl)=NN1C1=NC=CC=C1Cl CKAATYOECWZFCI-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- BIOZGFIBYVWPGR-UHFFFAOYSA-N N-(2-cyanopropan-2-yl)-N,3-dimethyl-2-nitrobenzamide Chemical compound C(#N)C(C)(C)N(C(C1=C(C(=CC=C1)C)[N+](=O)[O-])=O)C BIOZGFIBYVWPGR-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 241000256247 Spodoptera exigua Species 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 230000002745 absorbent Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- MAKFMOSBBNKPMS-UHFFFAOYSA-N 2,3-dichloropyridine Chemical compound ClC1=CC=CN=C1Cl MAKFMOSBBNKPMS-UHFFFAOYSA-N 0.000 description 1
- HLRRSBKJQCNOSY-UHFFFAOYSA-N 2-amino-3,5-dichloro-N-(2-cyanopropan-2-yl)-N-methylbenzamide Chemical compound NC1=C(C(=O)N(C(C)(C)C#N)C)C=C(C=C1Cl)Cl HLRRSBKJQCNOSY-UHFFFAOYSA-N 0.000 description 1
- FYPIIMYXBCWBPQ-UHFFFAOYSA-N 2-amino-5-cyano-3-methylbenzoic acid Chemical compound CC1=CC(C#N)=CC(C(O)=O)=C1N FYPIIMYXBCWBPQ-UHFFFAOYSA-N 0.000 description 1
- IBBKXPLJRYEYEG-UHFFFAOYSA-N 2-amino-5-cyano-N-(2-cyanopropan-2-yl)-N,3-dimethylbenzamide Chemical compound C(#N)C(C)(C)N(C(C1=C(C(=CC(=C1)C#N)C)N)=O)C IBBKXPLJRYEYEG-UHFFFAOYSA-N 0.000 description 1
- BAQHDZTXAXUXIB-UHFFFAOYSA-N 2-amino-N-(2-cyanopropan-2-yl)-N-methylbenzamide Chemical compound NC1=C(C(=O)N(C(C)(C)C#N)C)C=CC=C1 BAQHDZTXAXUXIB-UHFFFAOYSA-N 0.000 description 1
- MWFMGBPGAXYFAR-UHFFFAOYSA-N 2-hydroxy-2-methylpropanenitrile Chemical compound CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 description 1
- NKQVYJRZBVRXRU-UHFFFAOYSA-N 2-methyl-2-(methylamino)propanenitrile Chemical compound CNC(C)(C)C#N NKQVYJRZBVRXRU-UHFFFAOYSA-N 0.000 description 1
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 description 1
- MOXMPWAWQLBNGS-UHFFFAOYSA-N 5-bromo-2-(3-chloropyridin-2-yl)pyrazole-3-carbonyl chloride Chemical compound ClC(=O)C1=CC(Br)=NN1C1=NC=CC=C1Cl MOXMPWAWQLBNGS-UHFFFAOYSA-N 0.000 description 1
- UYQAQLWFQYZFJN-UHFFFAOYSA-N 5-chloro-2-(3-chloropyridin-2-yl)pyrazole-3-carbonyl chloride Chemical compound ClC(=O)C1=CC(Cl)=NN1C1=NC=CC=C1Cl UYQAQLWFQYZFJN-UHFFFAOYSA-N 0.000 description 1
- DGDAVTPQCQXLGU-UHFFFAOYSA-N 5437-38-7 Chemical compound CC1=CC=CC(C(O)=O)=C1[N+]([O-])=O DGDAVTPQCQXLGU-UHFFFAOYSA-N 0.000 description 1
- 239000005886 Chlorantraniliprole Substances 0.000 description 1
- IEPRKVQEAMIZSS-UHFFFAOYSA-N Di-Et ester-Fumaric acid Natural products CCOC(=O)C=CC(=O)OCC IEPRKVQEAMIZSS-UHFFFAOYSA-N 0.000 description 1
- IEPRKVQEAMIZSS-WAYWQWQTSA-N Diethyl maleate Chemical compound CCOC(=O)\C=C/C(=O)OCC IEPRKVQEAMIZSS-WAYWQWQTSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- JXFYQOXQANCVAS-UHFFFAOYSA-N N-(2-cyanopropan-2-yl)-N-methyl-2-nitrobenzamide Chemical compound [N+](=O)([O-])C1=C(C(=O)N(C(C)(C)C#N)C)C=CC=C1 JXFYQOXQANCVAS-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000003936 benzamides Chemical class 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- PSOVNZZNOMJUBI-UHFFFAOYSA-N chlorantraniliprole Chemical compound CNC(=O)C1=CC(Cl)=CC(C)=C1NC(=O)C1=CC(Br)=NN1C1=NC=CC=C1Cl PSOVNZZNOMJUBI-UHFFFAOYSA-N 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 238000003403 chloroformylation reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
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- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000003337 fertilizer Substances 0.000 description 1
- 230000005669 field effect Effects 0.000 description 1
- 235000019256 formaldehyde Nutrition 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100001225 mammalian toxicity Toxicity 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- LPKZSPQPPSEVSX-UHFFFAOYSA-N n-(cyanomethyl)benzamide Chemical class N#CCNC(=O)C1=CC=CC=C1 LPKZSPQPPSEVSX-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000005648 plant growth regulator Substances 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 102000042094 ryanodine receptor (TC 1.A.3.1) family Human genes 0.000 description 1
- 108091052345 ryanodine receptor (TC 1.A.3.1) family Proteins 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/90—Carboxylic acid amides having nitrogen atoms of carboxamide groups further acylated
- C07C233/92—Carboxylic acid amides having nitrogen atoms of carboxamide groups further acylated with at least one carbon atom of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
- C07C255/29—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton containing cyano groups and acylated amino groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
Abstract
a presente invenção revela um composto de n-alquil-n-cianoalquilbenzamida da fórmula geral i, um intermediário da fórmula geral ii usado para preparar o composto, em que r1 é selecionado a partir de halo ou c1-c3 alquila; r2 é selecionado a partir de halo ou cn; r3 é selecionado a partir de halo ou c1-c3 haloalquila; r4 é selecionado a partir de halo; r5 é selecionado a partir de h ou halo; r6 é selecionado a partir de c1-c3 alquila, c1-c3 haloalquila ou c1-c5 alcoxialquila; r7 é selecionado a partir de c1-c5 alquila; e r8 é selecionado a partir de hidrogênio ou c1-c5 alquila. em comparação com os compostos da técnica anterior, o composto da fórmula geral i apresenta uma atividade mais alta a uma baixa concentração. particularmente, o composto da presente invenção ainda apresenta 60% ou mais da atividade inseticida a uma concentração abaixo de 1 ppm. isso reduz bastante a quantidade do composto usado e o resíduo do composto em uma terra agrícola e, portanto, é ambientalmente amigável.the present invention discloses an n-alkyl-n-cyanoalkylbenzamide compound of general formula i, an intermediate of general formula ii used to prepare the compound, wherein r1 is selected from halo or c1-c3 alkyl; R2 is selected from Halo or CN; r3 is selected from halo or c1-c3 haloalkyl; r4 is selected from halo; r5 is selected from h or halo; r6 is selected from c1-c3 alkyl, c1-c3 haloalkyl or c1-c5 alkoxyalkyl; r7 is selected from c1-c5 alkyl; and r8 is selected from hydrogen or c1-c5 alkyl. Compared to prior art compounds, the compound of general formula i exhibits higher activity at a low concentration. particularly, the compound of the present invention still exhibits 60% or more insecticidal activity at a concentration below 1 ppm. This greatly reduces the amount of compost used and compost residue on an agricultural land and is therefore environmentally friendly.
Description
[001] A presente invenção se refere ao campo da técnica de inseticidas, e, particularmente, a um composto de N-alquil-N-cianoalquilbenzamida e o uso do mesmo.[001] The present invention relates to the field of insecticide art, and particularly to an N-alkyl-N-cyanoalkylbenzamide compound and the use thereof.
[002] A resistência de pragas tem sido um problema que intriga os trabalhadores de proteção de plantas. Para resolver esse problema, novos tipos de inseticidas precisam ser constantemente desenvolvidos. Os compostos de benzamida desenvolvidos pela DuPont são uma nova classe de compostos direcionados ao receptor de rianodina O composto representativo clorantraniliprol (Rynaxypyr™) mostra excelente atividade inseticida abrangente e efeitos de campo, baixa toxicidade para mamíferos e boa compatibilidade ambiental. O documento de patente n° WO 2008134969 revela compostos de N- cianoalquil-o-aminobenzamida, dos quais o Composto 1.14 (KC1) apresenta boa atividade inseticida. [002] Pest resistance has been a problem that intrigues plant protection workers. To solve this problem, new types of insecticides need to be constantly developed. The benzamide compounds developed by DuPont are a new class of compounds targeting the ryanodine receptor. The representative compound chlorantraniliprole (Rynaxypyr™) shows excellent comprehensive insecticidal activity and field effects, low mammalian toxicity, and good environmental compatibility. Patent document No. WO 2008134969 discloses N-cyanoalkyl-o-aminobenzamide compounds, of which Compound 1.14 (KC1) shows good insecticidal activity.
[004] Na técnica anterior, o composto de N- alquil-N-cianoalquilbenzamida mostrado na presente invenção não foi revelado.[004] In the prior art, the N-alkyl-N-cyanoalkylbenzamide compound shown in the present invention has not been disclosed.
[005] A presente invenção fornece um composto de N-alquil-N-cianoalquilbenzamida com uma estrutura inovadora e maior efeito inseticida, o que é útil no controle de pragas.[005] The present invention provides an N-alkyl-N-cyanoalkylbenzamide compound with an innovative structure and greater insecticidal effect, which is useful in pest control.
[006] As seguintes soluções técnicas são adotadas na presente invenção. Um composto de N-alquil-N- cianoalquilbenzamida da Fórmula Geral I é fornecido: [006] The following technical solutions are adopted in the present invention. An N-alkyl-N-cyanoalkylbenzamide compound of General Formula I is provided:
[007] Na Fórmula Geral I:[007] In General Formula I:
[008] R1 é selecionado a partir de halo ou C1-C3 alquila; R2 é selecionado a partir de halo ou CN; R3 é selecionado a partir de halo ou C1-C3 haloalquila; R4 é selecionado a partir de halo; R5 é selecionado a partir de H ou halo; R6 é selecionado a partir de C1-C3 alquila, C1-C3 haloalquila, ou C1-C5 alcoxialquila; R7 é selecionado a partir de C1-C5 alquila; e R8 é selecionado a partir de hidrogênio ou C1-C5 alquila. As propriedades físicas de alguns compostos da Fórmula Geral I são mostradas na Figura 1. Alguns compostos da Fórmula Geral I são testados por espectroscopia por 1HNMR. Os resultados da espectroscopia por 1HNMR (DMSO-d6, 300 MHz) são mostrados na Figura 3.[008] R1 is selected from halo or C1-C3 alkyl; R2 is selected from halo or CN; R3 is selected from halo or C1-C3 haloalkyl; R4 is selected from halo; R5 is selected from H or halo; R6 is selected from C1-C3 alkyl, C1-C3 haloalkyl, or C1-C5 alkoxyalkyl; R7 is selected from C1-C5 alkyl; and R8 is selected from hydrogen or C1-C5 alkyl. The physical properties of some compounds of General Formula I are shown in Figure 1. Some compounds of General Formula I are tested by 1HNMR spectroscopy. The 1HNMR spectroscopy results (DMSO-d6, 300 MHz) are shown in Figure 3.
[009] Os compostos preferenciais na presente invenção são os da Fórmula Geral I, nos quais[009] The preferred compounds in the present invention are those of General Formula I, in which
[010] R1 é selecionado a partir de cloro, bromo ou metila; R2 é selecionado a partir de cloro, bromo, flúor ou CN; R3 é selecionado a partir de cloro, bromo ou trifluorometila; R4 é selecionado a partir de cloro; R5 é selecionado a partir de H ou cloro; R6 é selecionado a partir de C1-C3 alquila, CH2OCH3, CH2O CH2CH3, CH2CH2OCH3, CF3, CH2CH2F, CH2CHF2, CH2CF3, CF2CF3 ou CF(CF3)2; R7 é selecionado a partir de metila; e R8 é selecionado a partir de hidrogênio ou metila.[010] R1 is selected from chlorine, bromine or methyl; R2 is selected from chlorine, bromine, fluorine or CN; R3 is selected from chlorine, bromine or trifluoromethyl; R4 is selected from chlorine; R5 is selected from H or chlorine; R6 is selected from C1-C3 alkyl, CH2OCH3, CH2O CH2CH3, CH2CH2OCH3, CF3, CH2CH2F, CH2CHF2, CH2CF3, CF2CF3 or CF(CF3)2; R7 is selected from methyl; and R8 is selected from hydrogen or methyl.
[011] Os compostos mais preferenciais são os da Fórmula Geral I, nos quais R1 é selecionado a partir de cloro, bromo ou metila; R2 é selecionado a partir de cloro, bromo, flúor ou CN; R3 é selecionado a partir de cloro ou bromo; R4 é selecionado a partir de cloro; R5 é selecionado a partir de H; R6 é selecionado a partir de metila; R7 é selecionado a partir de metila; e R8 é selecionado a partir de metila.[011] The most preferred compounds are those of General Formula I, in which R1 is selected from chlorine, bromine or methyl; R2 is selected from chlorine, bromine, fluorine or CN; R3 is selected from chlorine or bromine; R4 is selected from chlorine; R5 is selected from H; R6 is selected from methyl; R7 is selected from methyl; and R8 is selected from methyl.
[012] A presente invenção também envolve um intermediário útil na preparação direta do composto da Fórmula Geral I, que apresenta uma estrutura da Fórmula Geral II: [012] The present invention also involves an intermediate useful in the direct preparation of the compound of General Formula I, which has a structure of General Formula II:
[013] Na Fórmula Geral II:[013] In General Formula II:
[014] R1 é selecionado a partir de halo ou C1-C3 alquila; R2 é selecionado a partir de halo ou CN; R6 é selecionado a partir de C1-C3 alquila, C1-C3 haloalquila ou C1-C5 alcoxialquila; R7 é selecionado a partir de C1-C5 alquila; e R8 é selecionado a partir de hidrogênio ou C1-C5 alquila. As propriedades físicas de alguns compostos da Fórmula Geral II são mostradas na Figura 2.[014] R1 is selected from halo or C1-C3 alkyl; R2 is selected from halo or CN; R6 is selected from C1-C3 alkyl, C1-C3 haloalkyl or C1-C5 alkoxyalkyl; R7 is selected from C1-C5 alkyl; and R8 is selected from hydrogen or C1-C5 alkyl. The physical properties of some compounds of General Formula II are shown in Figure 2.
[015] Salvo indicação em contrário, os termos a seguir usados no relatório descritivo e reivindicações apresentam os significados discutidos abaixo.[015] Unless otherwise indicated, the following terms used in the specification and claims have the meanings discussed below.
[016] "Alquila" significa um grupo hidrocarboneto alifático saturado, incluindo formas lineares e ramificadas, como, por exemplo, metila, etila, propila, isopropila e semelhantes. "Haloalquila" significa um grupo no qual um grupo alquila é substituído com um ou mais átomos de halogênio, como, por exemplo, cloroetila, trifluorometila e semelhantes. "Alcóxi" significa um grupo com um átomo de oxigênio ligado à extremidade de um grupo alquila, como, por exemplo, metóxi, etóxi e similares.[016] "Alkyl" means a saturated aliphatic hydrocarbon group, including linear and branched forms, such as, for example, methyl, ethyl, propyl, isopropyl and the like. "Haloalkyl" means a group in which an alkyl group is substituted with one or more halogen atoms, such as, for example, chloroethyl, trifluoromethyl and the like. "Alkoxy" means a group with an oxygen atom attached to the end of an alkyl group, such as methoxy, ethoxy and the like.
[017] Doravante no presente documento, é mostrado um método típico de preparação da presente invenção, mas não se destina a limitar o escopo da presente invenção de forma alguma.[017] Hereinafter, a typical method of preparing the present invention is shown, but is not intended to limit the scope of the present invention in any way.
[018] O composto da Fórmula Geral I pode ser preparado pelo Esquema de Reação 1, em que os substituintes são conforme definidos acima, a menos que seja especificado de outra forma. [018] The compound of General Formula I can be prepared by Reaction Scheme 1, in which the substituents are as defined above, unless otherwise specified.
[019] O método do Esquema de Reação 1 inclui a reação de um composto da Fórmula Geral II com um composto da Fórmula Geral III na presença ou ausência de uma base para obter um composto da Fórmula Geral I.[019] The method of Reaction Scheme 1 includes reacting a compound of General Formula II with a compound of General Formula III in the presence or absence of a base to obtain a compound of General Formula I.
[020] A adição de uma quantidade apropriada de uma base é benéfica para a reação. Bases orgânicas úteis incluem: piridina, trietilamina, terc-butóxido de potássio, 4- dimetilaminopiridina ou N-metilmorfolina. Bases inorgânicas úteis incluem: hidreto de sódio, bicarbonato de sódio, carbonato de sódio, carbonato de potássio e hidróxido de sódio. A reação é adequadamente realizada em um solvente inerte, como, por exemplo, tetraidrofurano, acetonitrila, tolueno, diclorometano e semelhantes.[020] The addition of an appropriate amount of a base is beneficial to the reaction. Useful organic bases include: pyridine, triethylamine, potassium tert-butoxide, 4-dimethylaminopyridine or N-methylmorpholine. Useful inorganic bases include: sodium hydride, sodium bicarbonate, sodium carbonate, potassium carbonate and sodium hydroxide. The reaction is suitably carried out in an inert solvent, such as, for example, tetrahydrofuran, acetonitrile, toluene, dichloromethane and the like.
[021] Após a conclusão da reação, a mistura de reação que contém o produto pretendido é separada seguindo um método comum e, se necessário, purificada por recristalização ou cromatografia em coluna, obtendo, desse modo, o produto pretendido. Esses métodos estão bem documentados em literaturas, por exemplo, J. Org. Chem. 32, 3069 (1967).[021] After completion of the reaction, the reaction mixture containing the intended product is separated following a common method and, if necessary, purified by recrystallization or column chromatography, thereby obtaining the intended product. These methods are well documented in literatures, e.g., J. Org. Chem. 32, 3069 (1967).
[022] O composto da Fórmula Geral II também pode ser preparado pelo Esquema de Reação 2, em que os substituintes são conforme definidos acima, a menos que seja especificado de outra forma. [022] The compound of General Formula II can also be prepared by Reaction Scheme 2, in which the substituents are as defined above, unless otherwise specified.
[023] O composto da Fórmula Geral V pode ser preparado por um método geral conhecido (por exemplo, Organic Syntheses, 9, 32 (1929)). O composto da Fórmula Geral V é preparado com um reagente de cloroformilação disponível comercialmente, como, por exemplo, clorossulfóxido e cloreto de oxalila.[023] The compound of General Formula V can be prepared by a known general method (for example, Organic Syntheses, 9, 32 (1929)). The compound of General Formula V is prepared with a commercially available chloroformylation reagent, such as chlorosulfoxide and oxalyl chloride.
[024] Alguns dos compostos da Fórmula Geral IV ou IV’ estão disponíveis comercialmente e alguns são preparados por um método geral conhecido, por exemplo, como descrito em J. Am. Chem. Soc., 75, 4.841 a 4.842(1953), e Chemical Communications, 48(50), 6.253 a 6.255(2012).[024] Some of the compounds of General Formula IV or IV' are commercially available and some are prepared by a known general method, for example, as described in J. Am. Chem. Soc., 75, 4,841 to 4,842 (1953), and Chemical Communications, 48 (50), 6,253 to 6,255 (2012).
[025] O composto da Fórmula Geral V reage com o composto da Fórmula Geral IV para obter o composto da Fórmula Geral VI. Um método conhecido, por exemplo, como descrito in J. Am. Chem. Soc., 135(12), 4.628 a 4.631(2013), pode ser usado.[025] The compound of General Formula V reacts with the compound of General Formula IV to obtain the compound of General Formula VI. A known method, for example, as described in J. Am. Chem. Soc., 135(12), 4,628 to 4,631(2013), can be used.
[026] Um método típico inclui a redução da hidrogenação em um solvente hidroxílico, como, por exemplo, etanol, metanol e isopropanol, na presença de um catalisador metálico, como, por exemplo, Pd/C, óxido de platina ou Ni (por exemplo, Chinese Journal of Chemical Engineering, 24(9), 1.195 a 1.200 (2016)). Também pode ser preparado por redução com metais, como, por exemplo, pó de zinco e pó de ferro na presença de um catalisador ácido. Esses métodos são, de modo geral, descritos em literaturas, como, por exemplo, documento de patente WO 2010042699; e Dye Industry, 37(4): 16 a 18(2000):[026] A typical method includes reducing hydrogenation in a hydroxyl solvent, such as, for example, ethanol, methanol and isopropanol, in the presence of a metal catalyst, such as, for example, Pd/C, platinum oxide or Ni (e.g. example, Chinese Journal of Chemical Engineering, 24(9), 1195 to 1200 (2016)). It can also be prepared by reduction with metals, such as zinc powder and iron powder in the presence of an acid catalyst. These methods are generally described in literature, such as, for example, patent document WO 2010042699; and Dye Industry, 37(4): 16 to 18(2000):
[027] Em uma molécula orgânica, a substituição do átomo de hidrogênio (ou dos átomos de hidrogênio) por metila ou outros grupos alquila pode aumentar a solubilidade da lipossolubilidade da molécula. Pode ser sabido, a partir da análise de dados magnéticos nucleares, que a introdução de metila, na presente invenção, causou mudanças na disposição espacial de moléculas. A lipossolubilidade de uma molécula está intimamente relacionada à condução da molécula em plantas, insetos e outros organismos. Mudanças na estrutura espacial de uma molécula também afetam a capacidade de a molécula se ligar ao alvo. Esses dois fatores desempenham um papel importante na eficácia de um agente. Os efeitos da lipossolubilidade e as mudanças na estrutura espacial de uma molécula sobre a condutividade e a capacidade da molécula bioativa de se ligar a um alvo são imprevisíveis e podem ser conhecidos apenas após muitos esforços criativos.[027] In an organic molecule, replacing the hydrogen atom (or hydrogen atoms) with methyl or other alkyl groups can increase the lipid solubility of the molecule. It can be known from the analysis of nuclear magnetic data that the introduction of methyl in the present invention caused changes in the spatial arrangement of molecules. The lipid solubility of a molecule is closely related to the conduction of the molecule in plants, insects and other organisms. Changes in the spatial structure of a molecule also affect the molecule's ability to bind to its target. These two factors play an important role in the effectiveness of an agent. The effects of lipid solubility and changes in the spatial structure of a molecule on the conductivity and ability of the bioactive molecule to bind to a target are unpredictable and can be known only after many creative efforts.
[028] Verificou-se que, em comparação com os compostos benzamido-acetonitrila conhecidos, o composto da Fórmula Geral I da presente invenção apresenta uma atividade inseticida inesperadamente alta. Portanto, a presente invenção também envolve o uso do composto da Fórmula Geral I no controle de pragas.[028] It was found that, in comparison with known benzamido-acetonitrile compounds, the compound of General Formula I of the present invention presents an unexpectedly high insecticidal activity. Therefore, the present invention also involves the use of the compound of General Formula I in pest control.
[029] A presente invenção também envolve uma composição inseticida que apresenta o composto da Fórmula Geral I, como um ingrediente ativo. O teor em porcentagem em peso do ingrediente ativo na composição inseticida está entre 1 a 99%. A composição inseticida também compreende um carreador agrícola, silvicultural e higienicamente aceitável.[029] The present invention also involves an insecticidal composition that presents the compound of General Formula I as an active ingredient. The weight percentage content of the active ingredient in the insecticidal composition is between 1 and 99%. The insecticidal composition also comprises an agricultural, silvicultural and hygienically acceptable carrier.
[030] A composição da presente invenção pode ser aplicada na forma de uma formulação. O composto da Fórmula Geral I, como um ingrediente ativo, pode ser dissolvido ou disperso em um carreador ou formulado em uma formulação para facilitar a dispersão quando usado como um inseticida. Por exemplo, esses produtos químicos podem ser transformados em pós molháveis ou concentrados emulsificáveis. Nessas composições, pelo menos, um carreador líquido ou sólido é adicionado e um surfactante apropriado pode ser adicionado quando necessário.[030] The composition of the present invention can be applied in the form of a formulation. The compound of General Formula I, as an active ingredient, can be dissolved or dispersed in a carrier or formulated into a formulation to facilitate dispersion when used as an insecticide. For example, these chemicals can be made into wettable powders or emulsifiable concentrates. In such compositions, at least one liquid or solid carrier is added and an appropriate surfactant may be added when necessary.
[031] As soluções técnicas da presente invenção também incluem um método para controlar pragas aplicando uma composição inseticida da presente invenção às pragas ou seus meios de crescimento. De modo geral, uma quantidade efetiva mais adequada é de 10 a 1.000 g por hectare.[031] The technical solutions of the present invention also include a method for controlling pests by applying an insecticidal composition of the present invention to pests or their growth media. Generally speaking, a more suitable effective amount is 10 to 1,000 g per hectare.
[032] Para algumas aplicações, por exemplo, na agricultura, um ou mais fungicidas, inseticidas, herbicidas, reguladores de crescimento de plantas ou fertilizantes podem ser adicionados à composição inseticida da presente invenção, trazendo, desse modo, vantagens e efeitos adicionais.[032] For some applications, for example, in agriculture, one or more fungicides, insecticides, herbicides, plant growth regulators or fertilizers can be added to the insecticidal composition of the present invention, thereby bringing additional advantages and effects.
[033] A presente invenção apresenta as seguintes vantagens. A presente invenção revela dois tipos de compostos. Em comparação com os compostos da técnica anterior, o composto da Fórmula Geral I apresenta uma atividade mais alta a uma baixa concentração. Particularmente, o composto da presente invenção ainda apresenta 60% ou mais da atividade inseticida a uma concentração abaixo de 1 ppm. Isso reduz bastante a quantidade do composto usado e o resíduo do composto em uma terra agrícola e, portanto, é ambientalmente amigável.[033] The present invention has the following advantages. The present invention discloses two types of compounds. Compared to prior art compounds, the compound of General Formula I exhibits higher activity at a low concentration. Particularly, the compound of the present invention still exhibits 60% or more insecticidal activity at a concentration below 1 ppm. This greatly reduces the amount of compost used and compost residue on agricultural land and is therefore environmentally friendly.
[034] O composto da Fórmula Geral II é um intermediário para sintetizar o composto da Fórmula Geral III. O método da presente invenção para sintetizar os compostos da Fórmula Geral I e Fórmula Geral II apresenta uma rota de processo curta e um alto rendimento. A presente invenção fornece uma nova rota de síntese para o composto da Fórmula Geral I. A presente invenção resolve o problema da síntese inconveniente de compostos semelhantes na técnica anterior, reduz consideravelmente o custo de produção dos compostos da Fórmula Geral I, é mais adequada para aplicações industriais aplicações e reduz o custo de produção dos fabricantes.[034] The compound of General Formula II is an intermediate to synthesize the compound of General Formula III. The method of the present invention for synthesizing the compounds of General Formula I and General Formula II features a short process route and a high yield. The present invention provides a new synthesis route for the compound of General Formula I. The present invention solves the problem of inconvenient synthesis of similar compounds in the prior art, considerably reduces the production cost of compounds of General Formula I, is more suitable for industrial applications applications and reduces the production cost of manufacturers.
[035] A Figura 1 mostra as propriedades físicas de alguns compostos da Fórmula Geral I de acordo com a presente invenção.[035] Figure 1 shows the physical properties of some compounds of General Formula I according to the present invention.
[036] A Figura 2 mostra as propriedades físicas de alguns compostos da Fórmula Geral II de acordo com a presente invenção.[036] Figure 2 shows the physical properties of some compounds of General Formula II according to the present invention.
[037] A Figura 3 mostra os resultados dos testes de alguns compostos da Fórmula Geral I, de acordo com a presente invenção, por espectroscopia de 1HNMR (DMSO-d6, 300 MHz).[037] Figure 3 shows the test results of some compounds of General Formula I, according to the present invention, by 1HNMR spectroscopy (DMSO-d6, 300 MHz).
[038] A presente invenção é adicionalmente descrita em detalhes abaixo com referência a modalidades específicas, mas as modalidades não se destinam a limitar a presente invenção.[038] The present invention is further described in detail below with reference to specific embodiments, but the embodiments are not intended to limit the present invention.
[039] Composto 1.15: Síntese de N-(6-N-((2- cianopropan-2-il)-N-metilcarbamoil)-2, 4-diclorofenil)-1-(3- cloropiridina-2-il)-3-bromo-1H- pirazol-5-carboxamida (1) SÍNTESE DE 2-METIL-2-(METILAMINO)PROPIONITRILA [039] Compound 1.15: Synthesis of N-(6-N-((2-cyanopropan-2-yl)-N-methylcarbamoyl)-2, 4-dichlorophenyl)-1-(3-chloropyridin-2-yl)- 3-bromo-1H- pyrazole-5-carboxamide (1) SYNTHESIS OF 2-METHYL-2-(METHYLAMINO)PROPIONITRILE
[040] Foi adicionada acetona cianidrina (8,5 g, 0,1 mol) a um frasco de quatro gargalos de 50 ml e, em seguida, foi introduzido lentamente gás metilamina (3,1 g, 0,1 mol) à temperatura ambiente. Depois disso, a reação foi agitada continuamente à temperatura ambiente por 5 h e extraída com diclorometano (10 ml x 3). A fase orgânica foi combinada e seca sobre sulfato de sódio anidro. Em seguida, o solvente foi removido sob pressão reduzida para obter um líquido transparente incolor (6,18 g, 63,0% de rendimento). (2) SÍNTHESE DE CLORETO DE 2-NITROBENZOÍLA [040] Acetone cyanohydrin (8.5 g, 0.1 mol) was added to a 50 ml four-neck flask and then methylamine gas (3.1 g, 0.1 mol) was slowly introduced at temperature environment. After that, the reaction was stirred continuously at room temperature for 5 h and extracted with dichloromethane (10 ml x 3). The organic phase was combined and dried over anhydrous sodium sulfate. Then, the solvent was removed under reduced pressure to obtain a colorless transparent liquid (6.18 g, 63.0% yield). (2) SYNTHESIS OF 2-NITROBENZOYL CHLORIDE
[041] Ácido 2-nitrobenzóico (8,4 g, 0,05 mol), dicloroetano (100 ml), clorossulfóxido (17,8 g, 0,15 mol) e DMF (1 gota) foram adicionados sequencialmente a um frasco de gargalo único de 250 ml, aquecidos ao refluxo e reagidos por 3 h. Em seguida, o solvente foi removido sob pressão reduzida para obter um líquido amarelo (8,9 g, 95,9% de rendimento). O produto foi usado diretamente na próxima etapa, sem pós- tratamento adicional. (3) SÍNTESE DE 2-NITRO-N-METIL-N- (2-CIANOPROPAN-2- IL)BENZAMIDA [041] 2-Nitrobenzoic acid (8.4 g, 0.05 mol), dichloroethane (100 ml), chlorosulfoxide (17.8 g, 0.15 mol) and DMF (1 drop) were added sequentially to a vial of single neck of 250 ml, heated to reflux and reacted for 3 h. Then, the solvent was removed under reduced pressure to obtain a yellow liquid (8.9 g, 95.9% yield). The product was used directly in the next step, without additional post-treatment. (3) SYNTHESIS OF 2-NITRO-N-METHYL-N- (2-CYANOPROPAN-2- IL)BENZAMIDE
[042] 2-metil-2- (metilamina) propionitrila (4,9 g, 0,05 mol), diclorometano (20 ml) e trietilamina (5,1 g, 0,05 mol) foram adicionados sequencialmente a um frasco de quatro gargalos de 250 ml. Em seguida, foi adicionado cloreto de 2-nitrobenzoíla (8,9 g, 0,048 mol) em diclorometano (20 ml) gota a gota a 0 °C, e, então, reagiu continuamente por 2 h com agitação a 0 °C. A solução de reação foi adicionada com água (50 ml) e extraída com diclorometano (20 ml x 3). As fases orgânicas foram combinadas, lavadas com solução aquosa saturada de cloreto de sódio e secas sobre sulfato de sódio anidro. O solvente foi removido sob pressão reduzida para obter um sólido amarelo (9,1 g, 76,6% de rendimento). (4) SÍNTESE DE 2-AMINO-N-METIL-N- (2-CIANOPROPAN-2- IL)BENZAMIDA [042] 2-methyl-2-(methylamine) propionitrile (4.9 g, 0.05 mol), dichloromethane (20 ml) and triethylamine (5.1 g, 0.05 mol) were added sequentially to a vial of four 250 ml bottlenecks. Then, 2-nitrobenzoyl chloride (8.9 g, 0.048 mol) in dichloromethane (20 ml) was added dropwise at 0 °C, and then reacted continuously for 2 h with stirring at 0 °C. The reaction solution was added with water (50 ml) and extracted with dichloromethane (20 ml x 3). The organic phases were combined, washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a yellow solid (9.1 g, 76.6% yield). (4) SYNTHESIS OF 2-AMINO-N-METHYL-N- (2-CYANOPROPAN-2- IL)BENZAMIDE
[043] Água (20 ml), pó de Fe reduzido (2,2 g, 0,04 mol) e 30% de ácido clorídrico (1 ml) foram adicionados sequencialmente a um frasco de quatro gargalos de 100 ml, aquecidos lentamente a 80 °C e agitados por 30 minutos a 80 °C. Em seguida, 2-nitro-N-metil-N- (2-cianopropan-2- il)benzamida (2,5 g, 0,01 mol) foi adicionado em lotes, enquanto a temperatura foi mantida a não mais que 80 °C. Depois disso, a reação foi agitada continuamente a 80 °C até que a reação fosse concluída conforme indicado por HPLC. A solução de reação foi resfriada até à temperatura ambiente, adicionada com hidróxido de sódio (1,6 g) e filtrada por sucção. O bolo de filtração foi lavado com água quente e o filtrado coletado foi extraído com acetato de etila (2 x 100 ml). A fase orgânica foi lavada com água, solução saturada de carbonato de sódio e salmoura saturada, e seca sobre sulfato de sódio anidro. O solvente foi removido sob pressão reduzida para obter um líquido marrom (1,37 g, 63,3% de rendimento). (5) SÍNTESE DE N-(1-CIANOISOPROPIL)-N-METIL-2- AMINO-3, -5-DICLOROBENZAMIDA [043] Water (20 ml), reduced Fe powder (2.2 g, 0.04 mol) and 30% hydrochloric acid (1 ml) were added sequentially to a 100 ml four-neck flask, slowly heated to 80 °C and stirred for 30 minutes at 80 °C. Then, 2-nitro-N-methyl-N-(2-cyanopropan-2-yl)benzamide (2.5 g, 0.01 mol) was added in batches while the temperature was maintained at no more than 80° W. Thereafter, the reaction was stirred continuously at 80 °C until the reaction was completed as indicated by HPLC. The reaction solution was cooled to room temperature, added with sodium hydroxide (1.6 g) and filtered by suction. The filter cake was washed with hot water and the collected filtrate was extracted with ethyl acetate (2 x 100 ml). The organic phase was washed with water, saturated sodium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a brown liquid (1.37 g, 63.3% yield). (5) SYNTHESIS OF N-(1-CYANOISOPROPYL)-N-METHYL-2- AMINO-3, -5-DICHLOROBENZAMIDE
[044] 2-amino-N-metil-N-(2-cianopropan-2- il)benzamida (1,1 g, 5 mmol), N-clorossuccinimida (2,2 g, 12,5 mmol) e DMF (20 ml) foram adicionados sequencialmente a um frasco de quatro gargalos de 100 ml e reagiram com agitação à temperatura ambiente até que a reação fosse concluída conforme indicado por HPLC. A solução de reação foi despejada em água (100 ml) e extraída com acetato de etila (20 ml x 3). As fases orgânicas foram combinadas, lavadas com solução aquosa saturada de cloreto de sódio e secas sobre sulfato de sódio anidro. O solvente foi removido sob pressão reduzida para obter um sólido amarelo claro (1,1 g, 78,6% de rendimento). (6) SÍNTESE DE N-(6-N-((2-CIANOPROPAN-2-IL) -N- METILCARBAMOIL)-2, 4-DICLOROFENIL)-1-(3-CLOROPIRIDINA-2-IL)- 3-BROMO-1H- PIRAZOL-5-CARBOXAMIDA [044] 2-amino-N-methyl-N-(2-cyanopropan-2-yl)benzamide (1.1 g, 5 mmol), N-chlorosuccinimide (2.2 g, 12.5 mmol) and DMF ( 20 ml) were added sequentially to a 100 ml four-neck flask and reacted with stirring at room temperature until the reaction was complete as indicated by HPLC. The reaction solution was poured into water (100 ml) and extracted with ethyl acetate (20 ml x 3). The organic phases were combined, washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a light yellow solid (1.1 g, 78.6% yield). (6) SYNTHESIS OF N-(6-N-((2-CYANOPROPAN-2-YL) -N- METHYLCARBAMOYL)-2, 4-DICHLOROPHENYL)-1-(3-CHLOROPYRIDINE-2-YL)- 3-BROMINE -1H- PYRAZOLE-5-CARBOXAMIDE
[045] 2-amino-3,5-dicloro-N-metil-N-(2- cianopropan-2-il)benzamida (1 g, 0,00376 mol), tetraidrofurano (10 ml) e piridina (0,3 g, 0,00376 mol) foram adicionados sequencialmente a um frasco 50 ml de quatro gargalos. Cloreto de 2- (3-cloro-piridin-2-il)-5-bromo -2H-pirazol-3-carbonila (1,2 g, 0,00376 mol) (preparado de acordo com um método conforme descrito no documento de patente WO 02/070483) em tetraidrofurano (10 ml) foram adicionados gota a gota em um banho de gelo. A reação foi agitada durante a noite em um banho de gelo, durante o qual o progresso da reação foi rastreado por HPLC. A solução de reação foi despejada em água (50 ml) e extraída com diclorometano (3 x 20 ml). A fase orgânica foi lavada sequencialmente com solução saturada de carbonato de sódio, solução aquosa saturada de cloreto de sódio e água, e seca sobre sulfato de sódio anidro. O solvente foi removido sob pressão reduzida e o produto bruto resultante foi purificado por cromatografia em coluna (eluente: acetato de etila: éter de petróleo = 3:1), para obter um sólido branco (0,85 g, 41,9% de rendimento). EXEMPLO 2 COMPOSTO 1.1: SÍNTESE DE N-(2-N- ((2-CIANOPROPAN-2- IL)-N-METILCARBAMOIL)-4-CLORO-6-METILFENIL)-1-(3- CLOROPIRIDIN-2-IL)-3-BROMO-1H-PIRAZOL-5-CARBOXAMIDA (1) SÍNTESE DE CLORETO DE 2-NITRO-3-METILBENZOÍLA [045] 2-amino-3,5-dichloro-N-methyl-N-(2-cyanopropan-2-yl)benzamide (1 g, 0.00376 mol), tetrahydrofuran (10 ml) and pyridine (0.3 g, 0.00376 mol) were added sequentially to a 50 ml four-neck flask. 2-(3-Chloro-pyridin-2-yl)-5-bromo-2H-pyrazol-3-carbonyl chloride (1.2 g, 0.00376 mol) (prepared according to a method as described in the document patent WO 02/070483) in tetrahydrofuran (10 ml) were added dropwise into an ice bath. The reaction was stirred overnight in an ice bath, during which the progress of the reaction was tracked by HPLC. The reaction solution was poured into water (50 ml) and extracted with dichloromethane (3 x 20 ml). The organic phase was washed sequentially with saturated sodium carbonate solution, saturated aqueous sodium chloride solution and water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the resulting crude product was purified by column chromatography (eluent: ethyl acetate: petroleum ether = 3:1), to obtain a white solid (0.85 g, 41.9% performance). EXAMPLE 2 COMPOUND 1.1: SYNTHESIS OF N-(2-N- ((2-CYANOPROPAN-2- IL)-N-METHYLCARBAMOYL)-4-CHLORO-6-METHYLPHENYL)-1-(3- CHLOROPYRIDIN-2-IL) -3-BROMO-1H-PYRAZOLE-5-CARBOXAMIDE (1) SYNTHESIS OF 2-NITRO-3-METHYLBENZOYL CHLORIDE
[046] Ácido 2-nitro-3-metilbenzóico (5,4 g, 0,03 mol), dicloroetano (100 ml), clorossulfóxido (23,8 g, 0,2 mol) e DMF (1 gota) foram adicionados sequencialmente a um frasco de 250 ml de gargalo único, aquecidos ao refluxo e reagiram por 3 h. Em seguida, o solvente foi removido sob pressão elevada para obter um líquido marrom (5,7 g, 95,2% de rendimento). O produto foi usado diretamente na próxima etapa, sem pós-tratamento adicional. (2) SÍNTESE DE N-(1-CIANOISOPROPIL)-N-METIL-3- METIL-2-NITROBENZAMIDA [046] 2-Nitro-3-methylbenzoic acid (5.4 g, 0.03 mol), dichloroethane (100 ml), chlorosulfoxide (23.8 g, 0.2 mol) and DMF (1 drop) were added sequentially to a 250 ml single-neck flask, heated to reflux and reacted for 3 h. Then, the solvent was removed under high pressure to obtain a brown liquid (5.7 g, 95.2% yield). The product was used directly in the next step without additional post-treatment. (2) SYNTHESIS OF N-(1-CYANOISOPROPYL)-N-METHYL-3- METHYL-2-NITROBENZAMIDE
[047] Cloridrato de 2-metil-2- (metilamina)propionitrila (4,0 g, 0,03 mol), tetraidrofurano (10 ml), água (10 ml) e NaHCO3 (5,1 g, 0,06 mol) foram adicionados sequencialmente a um frasco de 250 ml de quatro gargalos. Cloreto de 2-nitro-3-metilbenzoíla (5,7 g) em tetraidrofurano (20 ml) foi adicionado gota a gota a -10 °C e, em seguida, reagiu continuamente por 2 h com agitação a -10 °C. A solução de reação foi adicionada com água (50 ml) e extraída com acetato de etila (20 ml x 3). As fases orgânicas foram combinadas, lavadas com solução aquosa saturada de cloreto de sódio e secas sobre sulfato de sódio anidro. O solvente foi removido sob pressão reduzida para obter um sólido marrom (4,4 g, 56,5% de rendimento). (3) SÍNTESE DE N-(1-CIANOISOPROPIL)-N-METIL-3- METIL-2-AMINOBENZAMIDA [047] 2-Methyl-2-(methylamine)propionitrile hydrochloride (4.0 g, 0.03 mol), tetrahydrofuran (10 ml), water (10 ml) and NaHCO3 (5.1 g, 0.06 mol ) were added sequentially to a 250 ml four-neck flask. 2-Nitro-3-methylbenzoyl chloride (5.7 g) in tetrahydrofuran (20 ml) was added dropwise at -10 °C and then reacted continuously for 2 h with stirring at -10 °C. The reaction solution was added with water (50 ml) and extracted with ethyl acetate (20 ml x 3). The organic phases were combined, washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a brown solid (4.4 g, 56.5% yield). (3) SYNTHESIS OF N-(1-CYANOISOPROPYL)-N-METHYL-3- METHYL-2-AMINOBENZAMIDE
[048] Água (20 ml), pó de Fe reduzido (2,2 g, 0,04 mol) e 30% de ácido clorídrico (1 ml) foram adicionados sequencialmente a um frasco de quatro gargalos de 100 ml, aquecidos lentamente a 80 °C e agitados por 30 minutos a 80 °C. Em seguida, N-(1-cianoisopropil)-N-metil-3-metil-2- nitrobenzamida (2,6 g, 0,01 mol) foi adicionado em lotes, enquanto a temperatura foi mantida a não mais que 80 °C. Depois disso, a reação foi agitada continuamente a 80 °C até que a reação fosse concluída conforme indicado por HPLC. A solução de reação foi resfriada até à temperatura ambiente, adicionada com hidróxido de sódio (1,6 g) e filtrada por sucção. O bolo de filtração foi lavado com água quente e o filtrado coletado foi extraído com acetato de etila (2 x 100 ml). A fase orgânica foi lavada com água, solução saturada de carbonato de sódio e salmoura saturada, e seca sobre sulfato de sódio anidro. O solvente foi removido sob pressão reduzida para obter um sólido marrom (1,68 g, 71,3% de rendimento). (4) SÍNTESE DE N-(1-CIANOISOPROPIL)-N-METIL-2- AMINO-3-METIL-5-CLOROBENZAMIDA [048] Water (20 ml), reduced Fe powder (2.2 g, 0.04 mol) and 30% hydrochloric acid (1 ml) were added sequentially to a 100 ml four-neck flask, slowly heated to 80 °C and stirred for 30 minutes at 80 °C. Then, N-(1-cyanoisopropyl)-N-methyl-3-methyl-2-nitrobenzamide (2.6 g, 0.01 mol) was added in batches, while the temperature was maintained at no more than 80 °C. . Thereafter, the reaction was stirred continuously at 80 °C until the reaction was completed as indicated by HPLC. The reaction solution was cooled to room temperature, added with sodium hydroxide (1.6 g) and filtered by suction. The filter cake was washed with hot water and the collected filtrate was extracted with ethyl acetate (2 x 100 ml). The organic phase was washed with water, saturated sodium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a brown solid (1.68 g, 71.3% yield). (4) SYNTHESIS OF N-(1-CYANOISOPROPYL)-N-METHYL-2- AMINO-3-METHYL-5-CHLOROBENZAMIDE
[049] N-(1-cianoisopropil)-N-metil-3-metil-2- aminobenzamida (1,6 g, 6,9 mmol), N-clorosuccinimida (1,4 g, 10,3 mmol) e DMF (20 ml) foram adicionados sequencialmente a um frasco de 100 ml de quatro gargalos e reagiram com agitação à temperatura ambiente até que a reação fosse concluída conforme indicado por HPLC. A solução de reação foi despejada em água (100 ml) e extraída com acetato de etila (20 ml x 3). As fases orgânicas foram combinadas, lavadas sequencialmente com solução aquosa saturada de cloreto de sódio e água, e secas sobre sulfato de sódio anidro. O solvente foi removido sob pressão reduzida para obter um sólido amarelo claro (1,52 g, 83,1% de rendimento). (5) SÍNTESE DE N-(2-N-((2-CIANOPROPAN-2-IL)-N- METILCARBAMOIL)-4-CLORO-6-METILFENIL)-1-(3-CLOROPIRIDIN-2- IL)-3-BROMO- 1H-PIRAZOL-5-CARBOXAMIDA [049] N-(1-cyanoisopropyl)-N-methyl-3-methyl-2-aminobenzamide (1.6 g, 6.9 mmol), N-chlorosuccinimide (1.4 g, 10.3 mmol) and DMF (20 ml) were added sequentially to a 100 ml four-neck flask and reacted with stirring at room temperature until the reaction was complete as indicated by HPLC. The reaction solution was poured into water (100 ml) and extracted with ethyl acetate (20 ml x 3). The organic phases were combined, washed sequentially with saturated aqueous sodium chloride solution and water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a light yellow solid (1.52 g, 83.1% yield). (5) SYNTHESIS OF N-(2-N-((2-CYANOPROPAN-2-YL)-N- METHYLCARBAMOYL)-4-CHLORO-6-METHYLPHENYL)-1-(3-CHLOROPIDIN-2- IL)-3 -BROMINE- 1H-PYRAZOLE-5-CARBOXAMIDE
[050] N-(1-cianoisopropil)-N-metil-2-amino-3- metil-5-clorobenzamida (0,3 g, 1 mmol), diclorometano (10 ml), trietilamina (0,1 g, 1 mmol) e 2-cloreto de (3-cloro-piridin- 2-il)-5-bromo-2H-pirazol-3-carbonila (0,32 g, 1 mmol) (preparado de acordo com um método como descrito no documento de patente WO 02/070483) foram adicionados sequencialmente a um frasco de gargalo único de 50 ml e agitados à temperatura ambiente, até que a reação fosse concluída conforme indicado por HPLC. A solução de reação foi despejada em água (50 ml) e extraída com diclorometano (3 x 20 ml). A fase orgânica foi lavada sequencialmente com solução saturada de carbonato de sódio, solução aquosa saturada de cloreto de sódio e água, e seca sobre sulfato de sódio anidro. O solvente foi removido sob pressão reduzida e o produto bruto resultante foi purificado por cromatografia em coluna (eluente: acetato de etila: éter de petróleo = 3:1), para obter um sólido branco (0,20 g, 36,1% de rendimento). EXEMPLO 3 COMPOSTO 1.6: SÍNTESE DE N-(2-N-((2-CIANOPROPAN-2- IL)-N-METILCARBAMOIL)-4-CIANO-6-METILFENIL)-1-(3- CLOROPIRIDIN-2-IL)-3-CLORO-1H-PIRAZOL-5-CARBOXAMIDA (1) SÍNTESE DE 2-AMINO-3-METIL-5-IODO-N-(1- CIANOISOPROPIL)-N-METILBENZAMIDA [050] N-(1-cyanoisopropyl)-N-methyl-2-amino-3-methyl-5-chlorobenzamide (0.3 g, 1 mmol), dichloromethane (10 ml), triethylamine (0.1 g, 1 mmol) and (3-chloro-pyridin-2-yl)-5-bromo-2H-pyrazol-3-carbonyl 2-chloride (0.32 g, 1 mmol) (prepared according to a method as described in the document WO 02/070483) were added sequentially to a 50 ml single-neck flask and stirred at room temperature until the reaction was completed as indicated by HPLC. The reaction solution was poured into water (50 ml) and extracted with dichloromethane (3 x 20 ml). The organic phase was washed sequentially with saturated sodium carbonate solution, saturated aqueous sodium chloride solution and water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the resulting crude product was purified by column chromatography (eluent: ethyl acetate: petroleum ether = 3:1), to obtain a white solid (0.20 g, 36.1% performance). EXAMPLE 3 COMPOUND 1.6: SYNTHESIS OF N-(2-N-((2-CYANOPROPAN-2- IL)-N-METHYLCARBAMOYL)-4-CYANO-6-METHYLPHENYL)-1-(3- CHLOROPYRIDIN-2-IL) -3-CHLORO-1H-PYRAZOL-5-CARBOXAMIDE (1) SYNTHESIS OF 2-AMINO-3-METHYL-5-IODO-N-(1-CYANOISOPROPYL)-N-METHYLBENZAMIDE
[051] N-(1-cianoisopropil)-N-metil-3-metil-2- aminobenzamida (76,3 g, 0,33 mol) e DMF (250 ml) foram adicionados sequencialmente a um frasco de quatro gargalos de 500 ml. Foi adicionado lentamente N-clorossuccinimida (78,2 g, 0,35 mol) com agitação à temperatura ambiente, foi aquecido a 75 °C e reagiu até que a reação fosse concluída conforme indicado por HPLC. A solução de reação foi despejada em água (500 ml) e uma grande quantidade de sólido foi precipitada, a qual foi filtrada por sucção e seca para obter um sólido em pó roxo claro (69,1 g, 58,6% de rendimento). (2) SÍNTESE DE ÁCIDO 2-AMINO-3-METIL-5-CIANOBENZÓICO [051] N-(1-cyanoisopropyl)-N-methyl-3-methyl-2-aminobenzamide (76.3 g, 0.33 mol) and DMF (250 ml) were added sequentially to a 500 ml four-neck flask. ml. N-chlorosuccinimide (78.2 g, 0.35 mol) was slowly added with stirring at room temperature, heated to 75 °C and reacted until the reaction was complete as indicated by HPLC. The reaction solution was poured into water (500 ml) and a large amount of solid was precipitated, which was filtered by suction and dried to obtain a light purple powder solid (69.1 g, 58.6% yield). . (2) SYNTHESIS OF 2-AMINO-3-METHYL-5-CYANOBENZOIC ACID
[052] 2-amino-3-metil-5-iodo-N-(1- cianoisopropil)-N-metilbenzamida (60 g, 0,17 mol), CuCN (33 g, 0,37 mol) e DMF (300 ml) foram adicionados sequencialmente a um frasco de quatro gargalos de 500 ml, aquecidos a 145 °C e reagiram até a que reação fosse concluída conforme indicado por HPLC. Após a maior parte do solvente ter sido removido, foram adicionados água (720 ml) e etilenodiamina (15,8 g). O material insolúvel foi removido por filtração com sucção e, em seguida, 30% de ácido clorídrico (64 g) foi adicionado lentamente ao filtrado para ajustar o pH a um ácido fracamente. Uma grande quantidade de um sólido branco foi precipitada e filtrada por sucção. O bolo de filtração foi seco para obter um sólido branco (18,8 g, 43,2 de rendimento). (3) SÍNTESE DE 3-CLORO-2-PIRIDINIL-HIDRAZINA [052] 2-amino-3-methyl-5-iodo-N-(1-cyanoisopropyl)-N-methylbenzamide (60 g, 0.17 mol), CuCN (33 g, 0.37 mol) and DMF (300 ml) were added sequentially to a 500 ml four-neck flask, heated to 145 °C and reacted until the reaction was completed as indicated by HPLC. After most of the solvent was removed, water (720 ml) and ethylenediamine (15.8 g) were added. Insoluble material was removed by suction filtration and then 30% hydrochloric acid (64 g) was slowly added to the filtrate to adjust the pH to a weakly acidic one. A large amount of a white solid was precipitated and filtered by suction. The filter cake was dried to obtain a white solid (18.8 g, 43.2 yield). (3) SYNTHESIS OF 3-CHLORO-2-PYRIDINYL-HYDRAZINE
[053] 2,3-dicloropiridina (185 g, 1,25 mol) foi adicionado a n-butanol (800 ml) e, em seguida, hidrato de hidrazina (315 g) foi adicionado, aquecido ao refluxo e o mesmo reagiu por 35 a 40 h. A solução de reação foi resfriada até à temperatura ambiente, filtrada e seca para obter um cristal branco (120 g, 66,9% de rendimento). (4) SÍNTESE DE 2-(3-CLORO-2-PIRIDIL)-5-CARBONILA- PIRAZOLONA-3-CARBOXILATO DE ETILA [053] 2,3-dichloropyridine (185 g, 1.25 mol) was added to n-butanol (800 ml) and then hydrazine hydrate (315 g) was added, heated to reflux and reacted for 35 to 40 hours. The reaction solution was cooled to room temperature, filtered and dried to obtain a white crystal (120 g, 66.9% yield). (4) SYNTHESIS OF 2-(3-CHLORO-2-PYRIDYL)-5-CARBONYL-PYRAZOLONE-3-ETHYL CARBOXYLATE
[054] Pedaços de sódio cortados (24 g, 1,04 mol) foram adicionados a etanol absoluto (920 g) em porções e aquecidos a refluxo naturalmente. Após o sódio estar completamente dissolvido, a solução foi resfriada abaixo de 40 °C e 3-cloro-2-piridinil-hidrazina (120 g, 0,836 mol) foi adicionado de cada vez. Foi adicionado maleato de dietila (210 g, 1,22 mol) gota a gota por 1 h enquanto a temperatura foi mantida a 40 a 45 °C. A reação foi continuada por 4 h enquanto a temperatura foi mantida a 40 a 45 °C. Em seguida, a solução de reação foi resfriada até a temperatura ambiente e despejada em ácido acético glacial em água fria em lotes com agitação. O etanol (650 a 700 ml) foi destilado sob pressão reduzida e, em seguida, a solução foi resfriada à temperatura ambiente, foi submetida a repouso e filtrada. O bolo de filtração foi lavado com etanol (65 ml x 2), coletado e seco para obter um produto finalizado (120 g). O filtrado e as lavagens foram combinados e concentrados sob pressão reduzida para remover quase todo o etanol e obter uma grande quantidade de uma solução verde escuro com sólido preto. A solução foi extraída com clorofórmio (200 ml), seca sobre sulfato de magnésio anidro, filtrada e concentrada até à secura. Tolueno (50 ml) foi adicionado e aquecido para obter uma solução uniforme. A solução foi resfriada até a temperatura ambiente, congelada em um frigorífico durante a noite, filtrada, lavada com tolueno (15 ml) e seca para obter um sólido verde escuro (9 g, 57,2% de rendimento total). (5) SÍNTESE DE 3-CLORO-1-(3-CLORO-2-PIRIDIL)-4,5- DIIDROPIRANO-5-CARBOXILATO DE ETILA [054] Cut pieces of sodium (24 g, 1.04 mol) were added to absolute ethanol (920 g) in portions and heated to reflux naturally. After the sodium was completely dissolved, the solution was cooled to below 40 °C and 3-chloro-2-pyridinylhydrazine (120 g, 0.836 mol) was added each time. Diethyl maleate (210 g, 1.22 mol) was added dropwise over 1 h while the temperature was maintained at 40 to 45 °C. The reaction was continued for 4 h while the temperature was maintained at 40 to 45 °C. Then, the reaction solution was cooled to room temperature and poured into glacial acetic acid in cold water in batches with stirring. Ethanol (650 to 700 ml) was distilled under reduced pressure and then the solution was cooled to room temperature, allowed to stand and filtered. The filter cake was washed with ethanol (65 ml x 2), collected and dried to obtain a finished product (120 g). The filtrate and washings were combined and concentrated under reduced pressure to remove almost all of the ethanol and obtain a large amount of a dark green solution with black solid. The solution was extracted with chloroform (200 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Toluene (50 ml) was added and heated to obtain a uniform solution. The solution was cooled to room temperature, frozen in a refrigerator overnight, filtered, washed with toluene (15 ml) and dried to obtain a dark green solid (9 g, 57.2% total yield). (5) SYNTHESIS OF 3-CHLORO-1-(3-CHLORO-2-PYRIDYL)-4,5- ETHYL DIHYDROPYRANE-5-CARBOXYLATE
[055] Oxicloreto de fósforo (109,8 g, 0,716 mol) foi adicionado a acetonitrila (430 g) e, em seguida, foi adicionado 2-(3-cloro-2-piridil)-5-carbonila-pirazolona-3- carboxilato de etila (134,5 g, 0,499 mol). A mistura foi aquecida ao refluxo e a mesma reagiu por 4 a 5 h. Em seguida, a solução de reação foi despejada em água gelada (1.200 g), extraída duas vezes com clorofórmio (400 ml) e lavada uma vez com 10% de solução aquosa de bicarbonato de sódio (300 ml). A fase orgânica foi separada, seca sobre sulfato de sódio anidro por 5 h, filtrada e concentrada até quase secura sob pressão reduzida. Etanol absoluto (200 ml) foi adicionado, aquecido a 60 °C e agitado uniformemente. A solução de reação foi removida enquanto quente, congelada durante a noite a -18 °C, filtrada, lavada com etanol anidro e seca para obter um cristal roxo claro (113,7 g, 79,1% de rendimento). (6) SÍNTESE DE 3-CLORO-1-(3-CLORO-2-PIRIDIL) PIRAZOL-5-CARBOXILATO DE ETILA [055] Phosphorus oxychloride (109.8 g, 0.716 mol) was added to acetonitrile (430 g) and then 2-(3-chloro-2-pyridyl)-5-carbonyl-pyrazolone-3- was added ethyl carboxylate (134.5 g, 0.499 mol). The mixture was heated to reflux and reacted for 4 to 5 h. Then, the reaction solution was poured into ice-cold water (1200 g), extracted twice with chloroform (400 ml), and washed once with 10% aqueous sodium bicarbonate solution (300 ml). The organic phase was separated, dried over anhydrous sodium sulfate for 5 h, filtered and concentrated to near dryness under reduced pressure. Absolute ethanol (200 ml) was added, heated to 60 °C and stirred uniformly. The reaction solution was removed while hot, frozen overnight at -18 °C, filtered, washed with anhydrous ethanol, and dried to obtain a light purple crystal (113.7 g, 79.1% yield). (6) SYNTHESIS OF 3-CHLORO-1-(3-CHLORO-2-PYRIDYL) PYRAZOLE-5-ETHYL CARBOXYLATE
[056] 3-cloro-1-(3-cloro-2-piridil)-4,5- diidropirano-5-carboxilato de etila foi adicionado (110,1 g, 0,382 mol) a acetonitrila (910 ml) e agitado até dissolver. Foram adicionados ácido sulfúrico concentrado (65,1 g, 0,664 mol) e, em seguida, persulfato de potássio (181 g, 0,67 mol). A mistura foi aquecida ao refluxo e reagiu por 15 h sob refluxo com agitação. Após o resfriamento, a solução de reação foi despejada em água gelada (1500 g), extraída duas vezes com clorofórmio (500 ml), lavada com bicarbonato de sódio a 10% (100 ml), seca sobre sulfato de magnésio anidro, filtrada e concentrada até a secura sob pressão reduzida para obter um sólido amarelo claro (85,8 g, 76,5% de rendimento). (7) SÍNTESE DE ÁCIDO 3-CLORO-1-(3-CLORO-2-PIRIDIL)- PIRAZOL-5-CARBOXÍLICO [056] Ethyl 3-chloro-1-(3-chloro-2-pyridyl)-4,5-dihydropyran-5-carboxylate was added (110.1 g, 0.382 mol) to acetonitrile (910 ml) and stirred until to dissolve. Concentrated sulfuric acid (65.1 g, 0.664 mol) and then potassium persulfate (181 g, 0.67 mol) were added. The mixture was heated to reflux and reacted for 15 h under reflux with stirring. After cooling, the reaction solution was poured into ice water (1500 g), extracted twice with chloroform (500 ml), washed with 10% sodium bicarbonate (100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a light yellow solid (85.8 g, 76.5% yield). (7) SYNTHESIS OF 3-CHLORO-1-(3-CHLORO-2-PYRIDYL)- PYRAZOLE-5-CARBOXYLIC ACID
[057] (57,2 g, 0,2 mol) foi suspenso em etanol (850 g) e aquecido a 50 °C. Em seguida, hidróxido de potássio (28,6 g, 0,511 mol) foi adicionado em água (250 ml) gota a gota por 30 minutos. A reação foi continuada a 50 a 55 °C por 5 h. Todo o etanol foi removido por concentração sob pressão reduzida e, em seguida, foi adicionada água (300 ml). Após resfriamento até a temperatura ambiente, e a solução ter sido extraída com acetato de etila (100 ml). A fase aquosa foi destilada sob pressão reduzida para remover o acetato de etila residual e resfriada à temperatura ambiente. Foi adicionado lentamente 15% de ácido clorídrico gota a gota com agitação até que o pH da solução fosse 2. A solução foi agitada continuamente por 2 h, filtrada, lavada com água e seca para obter um sólido amarelo claro (46,1 g, 89,3% de rendimento). (10) SÍNTESE DE CLORETO DE 3-BROMO-1-(3-CLORO-2- PIRIDIL)-PIRAZOL-5-FORMIL [057] (57.2 g, 0.2 mol) was suspended in ethanol (850 g) and heated to 50 °C. Then, potassium hydroxide (28.6 g, 0.511 mol) was added into water (250 ml) dropwise for 30 minutes. The reaction was continued at 50 to 55 °C for 5 h. All ethanol was removed by concentration under reduced pressure and then water (300 ml) was added. After cooling to room temperature, the solution was extracted with ethyl acetate (100 ml). The aqueous phase was distilled under reduced pressure to remove residual ethyl acetate and cooled to room temperature. 15% hydrochloric acid was slowly added dropwise with stirring until the pH of the solution was 2. The solution was stirred continuously for 2 h, filtered, washed with water and dried to obtain a light yellow solid (46.1 g, 89.3% yield). (10) SYNTHESIS OF 3-BROMO-1-(3-CHLORO-2-PYRIDYL)-PYRAZOLE-5-FORMYL CHLORIDE
[058] O ácido 3-cloro-1-(3-cloro-2-piridil)- pirazol-5-carboxílico (30 g, 0,33 mol) foi suspenso em diclorometano (1.500 ml) e, em seguida, foi adicionado DMF (1 ml). Após cerca de 4 h, cloreto de oxalilo (63 g, 0,496 mol) foi adicionado gota a gota à suspensão acima e reagiu durante a noite com agitação para obter uma solução límpida. A solução foi concentrada até a secura sob pressão reduzida para obter um semissólido, o qual foi selado para uso. (11) SÍNTESE DE N-(2-N-((2-CIANOPROPAN-2-IL)-N- METILCARBAMOIL)-4-CIANO-6-METILFENIL)-1-(3-CLOROPIRIDIN-2- IL)-3-CLORO-1H-PIRAZOL-5-CARBOXAMIDA [058] 3-Chloro-1-(3-chloro-2-pyridyl)-pyrazol-5-carboxylic acid (30 g, 0.33 mol) was suspended in dichloromethane (1,500 ml) and then added DMF (1 ml). After about 4 h, oxalyl chloride (63 g, 0.496 mol) was added dropwise to the above suspension and reacted overnight with stirring to obtain a clear solution. The solution was concentrated to dryness under reduced pressure to obtain a semisolid, which was sealed for use. (11) SYNTHESIS OF N-(2-N-((2-CYANOPROPAN-2-YL)-N- METHYLCARBAMOYL)-4-CYANO-6-METHYLPHENYL)-1-(3-CHLOROPYRIDIN-2- IL)-3 -CHLORO-1H-PYRAZOLE-5-CARBOXAMIDE
[059] N-(1-cianoisopropil)-N-metil-3-metil-2- amino-5-cianobenzamida (0,26 g, 1 mmol), acetonitrila (10 ml) e trietilamina (0,1 g, 1 mmol) foram adicionadas sequencialmente a um frasco de gargalo único de 50 ml e aquecidas ao refluxo. À temperatura de refluxo, cloreto de 2- (3-cloro-piridin-2-il)-5-cloro-2H-pirazol-3-carbonila (0,28 g, 1 mmol) foi adicionado de cada vez em acetonitrila (2 ml) e reagiu continuamente sob refluxo com agitação até que a reação fosse concluída conforme indicado por HPLC. A solução de reação foi despejada em água (50 ml) e extraída com diclorometano (3 x 20 ml). A fase orgânica foi lavada sequencialmente com solução saturada de carbonato de sódio, solução aquosa saturada de cloreto de sódio e água, e seca sobre sulfato de sódio anidro. O solvente foi removido sob pressão reduzida e o produto bruto resultante foi purificado por cromatografia em coluna (eluente: acetato de etila: éter de petróleo = 3:1), para obter um sólido branco (0,28 g, 56,7% de rendimento).[059] N-(1-cyanoisopropyl)-N-methyl-3-methyl-2-amino-5-cyanobenzamide (0.26 g, 1 mmol), acetonitrile (10 ml) and triethylamine (0.1 g, 1 mmol) were added sequentially to a 50 ml single-neck flask and heated to reflux. At reflux temperature, 2-(3-chloro-pyridin-2-yl)-5-chloro-2H-pyrazol-3-carbonyl chloride (0.28 g, 1 mmol) was added each time in acetonitrile (2 ml) and reacted continuously under reflux with stirring until the reaction was completed as indicated by HPLC. The reaction solution was poured into water (50 ml) and extracted with dichloromethane (3 x 20 ml). The organic phase was washed sequentially with saturated sodium carbonate solution, saturated aqueous sodium chloride solution and water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the resulting crude product was purified by column chromatography (eluent: ethyl acetate: petroleum ether = 3:1), to obtain a white solid (0.28 g, 56.7% performance).
[060] Os reagentes de teste foram todos dissolvidos em um solvente misto de acetona: N'N'- dimetilcarboxamida (1: 1) para dar uma solução de 1.000 mg/l. Foi adicionado 1% de Tween-80 como um emulsificante a cada solução. Essas soluções foram, então, diluídas com 1% de solução de Tween-20 em água para dar as concentrações desejadas das soluções de teste. Uma solução aquosa que contém 1% de Tween-20 foi usada como um controle.[060] The test reagents were all dissolved in a mixed solvent of acetone: N'N'-dimethylcarboxamide (1:1) to give a 1,000 mg/l solution. 1% Tween-80 was added as an emulsifier to each solution. These solutions were then diluted with 1% Tween-20 solution in water to give the desired concentrations of the test solutions. An aqueous solution containing 1% Tween-20 was used as a control.
[061] As folhas de couve foram perfuradas em discos de folhas com um diâmetro de 1 cm e pulverizadas com aerógrafo. Uma certa concentração do composto de teste foi pulverizada nos lados frontal e traseiro de cada disco de folha em um volume de 0,5 ml. Após secagem à sombra, para cada tratamento, 10 insetos de teste (larvas de 3° ínstar) foram inoculados e 3 replicações foram colocadas. Após o tratamento, eles foram cultivados em uma câmara a 25 °C com uma umidade relativa de 60% a 70% no escuro. Após 120 h, o número de insetos sobreviventes foi investigado para calcular a mortalidade.[061] The cabbage leaves were punched into leaf discs with a diameter of 1 cm and sprayed with an airbrush. A certain concentration of the test compound was sprayed on the front and back sides of each leaf disc in a volume of 0.5 ml. After drying in the shade, for each treatment, 10 test insects (3rd instar larvae) were inoculated and 3 replicates were placed. After treatment, they were grown in a chamber at 25 °C with a relative humidity of 60% to 70% in the dark. After 120 h, the number of surviving insects was investigated to calculate mortality.
[062] Quando a concentração da solução reagente é de 10 ppm, alguns compostos, como, por exemplo, 1,1, 1,15, 1,23, 1,32 e 1,33, apresentam um melhor efeito de controle sobre Spodoptera exigua, alcançando mais de 80%.[062] When the concentration of the reagent solution is 10 ppm, some compounds, such as 1.1, 1.15, 1.23, 1.32 and 1.33, have a better control effect on Spodoptera exigua, reaching more than 80%.
[063] As folhas de couve que não tinham sido expostas a inseticidas foram cortadas em discos de folha de cerca de 40 mm2 com tesoura. Os discos de folha foram imersos em cada solução do composto por 30 s. Em seguida, os discos de folha foram colocados em papel absorvente e secos ao ar até que não houvesse manchas de água óbvias nos discos de folha. Os discos de folha embebidos com os reagentes foram colocados em uma placa de Petri (7 cm), cada placa de Petri apresentando 3 discos de folha. As larvas de 3° ínstar de Spodoptera litura criadas nas plantas de couve internas foram cuidadosamente recolhidas com um pincel e colocadas nos discos de folha na placa de Petri, sendo que cada placa de Petri apresenta 10 a 15 insetos. Após a inoculação dos insetos, a placa de Petri foi coberta e colocada em uma câmara de cultivo de insetos a 25 °C com um fotoperíodo de 16 horas de luz/8 horas de escuridão. Após 120 h, o número de insetos sobreviventes foi investigado para calcular a mortalidade.[063] Cabbage leaves that had not been exposed to insecticides were cut into leaf discs of about 40 mm2 with scissors. The leaf discs were immersed in each compound solution for 30 s. Then, the leaf discs were placed on absorbent paper and air-dried until there were no obvious water stains on the leaf discs. The leaf discs soaked with the reagents were placed in a Petri dish (7 cm), each Petri dish showing 3 leaf discs. The 3rd instar larvae of Spodoptera litura reared on indoor cabbage plants were carefully collected with a brush and placed on the leaf discs in the Petri dish, with each Petri dish containing 10 to 15 insects. After insect inoculation, the Petri dish was covered and placed in an insect culture chamber at 25°C with a 16-h light/8-h dark photoperiod. After 120 h, the number of surviving insects was investigated to calculate mortality.
[064] Alguns resultados de teste são como os seguintes:[064] Some test results are as follows:
[065] Quando a concentração da solução reagente é de 4 ppm, a mortalidade de larvas de 3° instar de Spodoptera litura causada por alguns compostos, como, por exemplo, 1,1, 1,9, 1,15, 1,23, 1,32 e 1,33, é de 80% ou mais.[065] When the concentration of the reagent solution is 4 ppm, the mortality of 3rd instar larvae of Spodoptera litura caused by some compounds, such as, for example, 1.1, 1.9, 1.15, 1.23 , 1.32 and 1.33, is 80% or more.
[066] Quando a concentração da solução reagente é de 1 ppm, a mortalidade de larvas de 3° ínstar de Spodoptera litura causada por alguns compostos, como, por exemplo, 1,1, 1,9, 1,15 e 1,23, é de 80% ou mais.[066] When the concentration of the reagent solution is 1 ppm, the mortality of 3rd instar larvae of Spodoptera litura caused by some compounds, such as 1.1, 1.9, 1.15 and 1.23 , is 80% or more.
[067] Os discos de folha de couve frescos preparados foram imersos em uma certa concentração da solução do composto de teste por 10 segundos, removidos e secos naturalmente. Uma placa de 24 poços foi usada, um disco de folha tratado foi colocado em cada poço e uma larva de Helicoverpa armigera de terceiro ínstar foi inoculada e mantida hidratada. Após 120 h, o número de insetos sobreviventes foi investigado para calcular a mortalidade.[067] The prepared fresh cabbage leaf discs were immersed in a certain concentration of the test compound solution for 10 seconds, removed and dried naturally. A 24-well plate was used, a treated leaf disc was placed in each well and a third instar Helicoverpa armigera larva was inoculated and kept hydrated. After 120 h, the number of surviving insects was investigated to calculate mortality.
[068] Alguns resultados de teste são como os seguintes:[068] Some test results are as follows:
[069] Quando a concentração da solução reagente é de 4 ppm, a mortalidade de larvas de 3° ínstar de Helicoverpa armigera causada por alguns compostos, como, por exemplo, 1,1, 1,15, 1,32 e 1,33, é de 80% ou mais.[069] When the concentration of the reagent solution is 4 ppm, the mortality of 3rd instar larvae of Helicoverpa armigera caused by some compounds, such as 1.1, 1.15, 1.32 and 1.33 , is 80% or more.
[070] Quando a concentração da solução reagente é de 1 ppm, a mortalidade de larvas de 3° instar de Helicoverpa armigera causada por alguns compostos, como, por exemplo, 1,1, 1,5, 1,15 e 1,33, é de 80% ou mais.[070] When the concentration of the reagent solution is 1 ppm, the mortality of 3rd instar larvae of Helicoverpa armigera caused by some compounds, such as 1.1, 1.5, 1.15 and 1.33 , is 80% or more.
[071] As mudas de arroz que não tinham sido expostas a inseticidas foram arrancadas e o solo foi lavado desde a raiz. Após não haver manchas de água óbvias nos discos de folha, os caules e as folhas das mudas foram imersos em diferentes concentrações de soluções de reagente (onde a solução de reagente estava contida em um tubo de ensaio e o caule e as folhas foram imersos para baixo). Após imersão por 30 s, eles foram retirados, colocados em papel absorvente e secos ao ar até que não houvesse manchas de água nas folhas. O papel de filtro foi colocado em uma placa de Petri (7 cm) e umedecido com água limpa. A placa de Petri foi invertida até que não caíssem gotas de água. As folhas foram cortadas das mudas tratadas em segmentos de folhas que apresentam substancialmente o mesmo diâmetro que a placa de Petri. Os segmentos de folha foram espalhados no papel de filtro na placa de Petri, sendo que cada placa de Petri apresenta 15 a 20 segmentos de folha.[071] Rice seedlings that had not been exposed to insecticides were uprooted and the soil was washed from the roots. After there were no obvious water stains on the leaf discs, the stems and leaves of the seedlings were immersed in different concentrations of reagent solutions (where the reagent solution was contained in a test tube and the stem and leaves were immersed to low). After soaking for 30 s, they were removed, placed on absorbent paper and air-dried until there were no water stains on the leaves. The filter paper was placed in a Petri dish (7 cm) and moistened with clean water. The Petri dish was inverted until no drops of water fell. Leaves were cut from the treated seedlings into leaf segments having substantially the same diameter as the Petri dish. The leaf segments were spread on the filter paper in the Petri dish, with each Petri dish having 15 to 20 leaf segments.
[072] As larvas de 3° a 4° ínstar de Cnaphalocrocis medinalis criadas na planta de trigo interna foram cuidadosamente recolhidas com um pincel e colocadas nos segmentos de folha da placa de Petri, sendo que cada placa de Petri apresenta 10 insetos. Após a inoculação dos insetos, a placa de Petri foi coberta e colocada em uma câmara de cultivo de insetos a 25 °C com um fotoperíodo de 16 horas de luz/8 horas de escuridão. A morte de Cnaphalocrocis medinalis foi investigada 72 h após a inoculação dos insetos.[072] The 3rd to 4th instar larvae of Cnaphalocrocis medinalis raised on the indoor wheat plant were carefully collected with a brush and placed on the leaf segments of the Petri dish, with each Petri dish containing 10 insects. After insect inoculation, the Petri dish was covered and placed in an insect culture chamber at 25°C with a 16-h light/8-h dark photoperiod. The death of Cnaphalocrocis medinalis was investigated 72 h after insect inoculation.
[073] Alguns resultados de teste são como os seguintes:[073] Some test results are as follows:
[074] Quando a concentração da solução reagente é de 20 ppm, a mortalidade de larvas de 3° a 4° instar de Cnaphalocrocis medinalis causada por alguns compostos, como, por exemplo, 1,1, 1,9, 1,15, 1,23, 1,32 e 1,33, é de 80% ou mais.[074] When the concentration of the reagent solution is 20 ppm, the mortality of 3rd to 4th instar larvae of Cnaphalocrocis medinalis caused by some compounds, such as, for example, 1.1, 1.9, 1.15, 1.23, 1.32 and 1.33, is 80% or more.
[075] Quando a concentração da solução de reagente é de 10 ppm, a mortalidade de larvas de 3° a 4° ínstar de Cnaphalocrocis medinalis causada por alguns compostos, como, por exemplo, 1,1, 1,15 e 1,32, é de 80% ou mais.[075] When the concentration of the reagent solution is 10 ppm, the mortality of 3rd to 4th instar larvae of Cnaphalocrocis medinalis caused by some compounds, such as 1.1, 1.15 and 1.32 , is 80% or more.
[076] Foram usadas larvas de 3° ínstar de Plutella xylostella. As couves foram lavadas, secas ao ar, perfuradas em discos de folha, imersas em soluções de reagente por 10 segundos, retiradas, secas naturalmente e colocadas em uma placa de Petri. 10 larvas de terceiro ínstar de Plutella xylostella foram inoculadas em cada placa de Petri e três replicações foram colocadas. O número de mortes em 3 dias foi investigado e a mortalidade foi calculada.[076] 3rd instar larvae of Plutella xylostella were used. The cabbages were washed, air dried, punched into leaf discs, immersed in reagent solutions for 10 seconds, removed, dried naturally and placed in a Petri dish. 10 third instar larvae of Plutella xylostella were inoculated into each Petri dish and three replicates were placed. The number of deaths within 3 days was investigated and mortality was calculated.
[077] Alguns resultados de teste são como os seguintes:[077] Some test results are as follows:
[078] Quando a concentração da solução de reagente é de 1 ppm, a mortalidade de Plutella xylostella causada por alguns compostos, como, por exemplo, 1,1, 1,9, 1,15, 1,23, 1,24, 1,28 a 1,30, 1,32 e 1,33, é de 90% ou mais.[078] When the concentration of the reagent solution is 1 ppm, the mortality of Plutella xylostella caused by some compounds, such as 1.1, 1.9, 1.15, 1.23, 1.24, 1.28 to 1.30, 1.32 and 1.33, is 90% or more.
[079] De acordo com o método acima, os Compostos Comparativos KC1 (Composto 1,14 no documento de patente WO 2008134969) e KC2 (Composto 1,18 no documento de patente WO 2008134969) na técnica anterior, que apresentam estrutura mais próxima do composto da presente invenção, foram testados quanto à atividade inseticida em Plutella xylostella. Os resultados experimentais são mostrados na Tabela abaixo.[079] According to the above method, the Comparative Compounds KC1 (Compound 1,14 in patent document WO 2008134969) and KC2 (Compound 1,18 in patent document WO 2008134969) in the prior art, which have a structure closer to the compound of the present invention, were tested for insecticidal activity on Plutella xylostella. The experimental results are shown in the Table below.
[080] Comparação paralela da atividade inseticida do Composto 1,15 da presente invenção com os Compostos KC1 e KC2 conhecidos em Plutella xylostella (% de mortalidade) [080] Parallel comparison of the insecticidal activity of Compound 1.15 of the present invention with known Compounds KC1 and KC2 on Plutella xylostella (% mortality)
[081] Pode ser observado pelos dados na Tabela acima que, quando usado na matança de Plutella xylostella, em comparação com o Composto KC1 e o Composto KC2 revelados na técnica anterior, o composto da presente invenção ainda apresenta atividade mais alta a uma concentração inferior a 1 ppm. Em comparação com os resultados de teste de KC1 e KC2, o composto da presente invenção apresenta uma dosagem mais baixa, mas uma atividade maior. A fórmula estrutural do KC2 é como a seguinte: [081] It can be seen from the data in the Table above that, when used in killing Plutella xylostella, compared to Compound KC1 and Compound KC2 disclosed in the prior art, the compound of the present invention still shows higher activity at a lower concentration at 1 ppm. Compared with the test results of KC1 and KC2, the compound of the present invention has a lower dosage but higher activity. The structural formula of KC2 is as follows:
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